Cancer Stem Cells and Tumor Microenvironment Group

Introduction

Cancer stem cells (CSCs), also known as tumor-initiating cells or tumor-propagating cells, constitute a biologically unique subset of stem-like cells within the bulk tumor cell population. These cells are believed to be important in metastasis and chemoresistance, and they are hypothesized to be key drivers of the multistep process of oncogenesis, giving rise to the clonogenic core of tumor tissues. In my laboratory, we study CSCs in the context of pancreatic ductal adenocarcinoma (PDAC), the 4th leading cause of cancer related deaths in developed countries. I am running a combined basic and translation research program, which synergistically combines studies on the biology of mouse and human CSCs, including their in vivo microenvironment, in order to enhance our understanding of the regulatory machinery of CSCs. Specifically, the avenues of research that my laboratory is pursuing are:

1) The identification and characterization of new biomarkers for the detection of CSCs from different solid tumors. We have recently discovered a new inherent biomarker present in CSCs across several solid tumors. This biomarker, known as autofluorescence, is the result of riboflavin accumulation in ABCG2-coated intracellular vesicles exclusively found in CSCs. We are currently using autofluorescence as a means of isolating CSCs for in depth biological and molecular characterization studies.

2) The identification of proteins that govern key CSC phenotypes, such as “stemness", epithelial to mesenchymal transition (EMT), oxidative phosphorylation (i.e. mitochondrial respiration) and chemoresistance. We have discovered that the Interferon Stimulated Gene 15 (ISG15) is not only up-regulated in CSCs, but its function as a Ubiquitin-like modifier is necessary for many CSCs biological processes.

3) Comprehensively understand the cellular make-up of the CSC niche and the larger more complex tumor microenvironment, specifically the role of tumor-associated macrophages (TAMs) in "activating" CSCs, with respect to the different environmental proteins they can secrete in response to cues from the tumor and how these proteins alter the function of the CSCs at the level of EMT and chemoresistance.



RECENT PUBLICATIONS
Our group has recently published several important papers and reviews in the cancer stem cell field:

1) Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase. Nature Medicine. 2018 Jul 24(7):954-960. PMID29808009
2) Current perspectives on the crosstalk between lung cancer stem cells and cancer-associated fibroblasts. Crit Rev Oncol Hematol. 2018 May;125:102-110. PMID29650269
3) The Ever-Evolving Concept of the Cancer Stem Cell in Pancreatic Cancer. Cancers. 2018 Jan 26;10(2). pii: E33. PMID29373514
4) Saa3 is a key mediator of the protumorigenic properties of cancer-associated fibroblasts in pancreatic tumors. Proc Natl Acad Sci USA (PNAS). 2018 Feb 6;115(6):E1147-E1156. PMID29351990
5) A current perspective on cancer immune therapy: step-by-step approach to constructing the magic bullet. Clin Transl Med. 2017 Dec;6(1):3. PMID28050779
6) GATA6 regulates EMT and tumour dissemination, and is a marker of response to adjuvant chemotherapy in pancreatic cancer. Gut. 2017 Sep;66(9):1665-1676. PMID27325420
7) Current evidence for cancer stem cells in gastrointestinal tumors and future research perspectives. Crit Rev Oncol Hematol. 2016 Nov;107:54-71. PMID27823652
8) DNMT1 inhibition reprograms pancreatic cancer cells via upregulation of the miR-17-92cluster. Cancer Research. 2016 Aug 1;76(15):4546-58. PMID27261509
9) The ever-changing landscape of pancreatic cancer stem cells. Pancreatology. 2016 Apr 14. pii: S1424-3903(16)30018-7. PMID27161173
10) Cancer Stem Cells and Macrophages: Implications in Tumor Biology and Therapeutic Strategies. Mediators of Inflammation. 2016:9012369. PMID26980947
11) MYC/PGC-1α Balance Determines the Metabolic Phenotype and Plasticity of Pancreatic Cancer Stem Cells. Cell Metabolism. 2015 Oct 6;22(4):590-605. PMID26365176
12) The miR-17-92 cluster counteracts quiescence and chemoresistance in a distinct subpopulation of pancreatic cancer stem cells. Gut. 2015 Dec;64(12):1936-48. PMID25887381
13) Microenvironmental hCAP-18/LL-37 promotes pancreatic ductal adenocarcinoma by activating its cancer stem cell compartment. Gut. 2015 Dec;64(12):1921-35. PMID25841238
14) ISG15 is a critical microenvironmental factor for pancreatic cancer stem cells. Cancer Research. 2014 Dec 15;74(24):7309-20. PMID25368022
15) Intracellular autofluorescence: a biomarker for epithelial cancer stem cells. Nature Methods. 2014 Nov;11(11):1161-9. PMID25262208

FULL LIST OF PUBLICATIONS



FUNDING
Our laboratory is currently funded by several national and international grants, including:

1) Titulo: Identification of pancreatic cancer immune escape receptors.
Funding Source: Asociación Cáncer de Páncreas (ACANPAN)

2) Project Title: A multi-faceted approach to treating pancreatic cancer.
Funding Source: Asociación Española Contra el Cáncer (AECC), Grupos Coordinados Estables 2016: CNIO (Dr. Mariano Barbacid), IRyCIS (Dr. Alfredo Carrato) and UAM (Dr. Bruno Sainz)

3) Project Title: Targeting ISG15, an Achilles' heel of cancer stem cells.
Funding Source: CONquer CanCER Now Award, Concern Foundation, LA, CA, USA

4) Project Title: Proyecto FIS - Development of a liquid biopsy assay to isolate circulating cancer stem cells in the blood for their characterization and validation as a biomarker for early detection of pancreatic cancer
Funding Source: ISCII & Spanish Ministry of Innovation & Competiveness (MINECO)

5) Project Title: Development of a state-of-the art liquid biopsy assay for the detection of circulating cancer stem cells fused to macrophages in human blood samples
Funding Source: Thermo Fisher Scientific, Attune® NxT Acoustic Flow

6) Project Title: CLIP Grant: Role of the innate immune system in promoting cancer stem cells
Funding Source: Cancer Research Institute, NY, NY, USA

7) Project Title: Ramón y Cajal Merit Award
Funding Source: Spanish Ministry of Innovation & Competiveness (MINECO)



LINKS
We collaborate in several European initiatives and are part of the national Spanish network of health research centers:

EUPancreas - a COST Action (BM1204) initiative

Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS)

PDAC-AECC


Sainz Anding, Bruno
Investigador Contratado



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